Remedies for multiple sclerosis

ABSTRACT

A medicine for treatment of multiple sclerosis comprising, as an effective component, ibudilast represented by the chemical formula (1) below. Ibudilast is effective to experimental autoimmune encephalomyelitis by oral administration, and is effective to multiple sclerosis which is a disease of a central nervous system.

This application is a 371 of PCT/JP98/03548 filed Aug. 10, 1998.

TECHNICAL FIELD

The present invention relates to a novel use of a medicine for multiplesclerosis.

TECHNICAL BACKGROUND

Multiple sclerosis is a disease of the central nervous system, which isslowly progressive and is characterized by diffuse patches ofdemyelination in the brain and spinal cord, resulting in multiple andvaried neurogic symptoms and signs, usually with repeated relapse andremission. The cause is unknown but an immunologic abnormality issuspected, with few clues presently indicating a specific mechanism (THEMERCK MANUAL, 16th EDITION, 1993 MERCK & CO.).

There are more multiple sclerosis cases in Europe and the United Statesthan in Japan. In Japan, adrenocortical steroid, or vitamin B₁₂ is usedfor the therapy (Konnichi no Chiryo Shishin (TODAY'S THERAPY), 1995,Igaku Shoin K.K.). Myzoribine, which is an immunosuppressive agent, andinterferon β1b are investigated as novel medicines (Asu no Shinyaku (NewMedicine of Tomorrow), 1997, Technomic K.K.).

In Europe and the United States, where there are many patients with thisdisease, fundamental and clinical researches are being conductedactively. As the pharmacotherapy, interferon β is mainly investigated,and injectables of interferon β are supplied to clinical sites (SCRIP,No2223 p20 Apr. 15, 1997: SCRIP, No2227 p21 Apr. 29, 1997). In Europeand the United States, the interferon β is given, to patients withrelapsing-remitting multiple sclerosis, subcutaneously in high dosesevery other day to decrease the frequency of neurological exacerbation(THE MERCK MANUAL, 16th EDITION, 1993, MERCK & CO.,INC). However, sincethe interferon β is expensive and should be administered for along-term, such medical treatment becomes costly. So as to gain thehigher medicinal compliance ratio, and less frequency of hospitalattendance for higher quality of life of the patient, an orallyadministrable medicine has been desired.

Adrenocortical steroid can be administered orally for the therapy.However, the use of the adrenocortical steroid should be limited toremission of acute attack or the like since long-term of administrationthereof may cause a side effect.

In recent years, pentoxifylline, and rolipram, which are respectively aninhibitor against an intracellular enzyme phosphodiesterase (hereinafterreferred to as PDE), are reported to be possibly effective (Rott et al.,Eur.J.Immunol., 23,p1745,1993; Nataf et al., Acta Neurol.Scand.,88,p97,1993; Genain et al., Proc.Natl.Acad.Sci., 92,3601,1995; Sommer etal., Nature Med., 1,p244,1995; Jung et al., J.Neuroimmunol., 68,p1,1996; and Okuda et al., Immunopharmacol., 35,p141,1996). Oraladministration of pentoxifylline was practically tested by multiplesclerosis patients, but the results of the evaluation for the medicaleffectiveness are not consistent (Rieckmann et al., J.Neurol.,242(Suppl.2),S112,1995; van Oosten et al., J.Neurol., 242(Suppl.2),S-119,1995; Myers et al., Neurol., 45(Suppl.4), A419,1995); Rieckmannet al., J.Neuroimmunol., 64,p193,1996). Therefore, a medicine isdemanded increasingly which is more effective and can be administeredorally.

With the aforementioned background, a medicine for multiple sclerosis isdemanded which is suitable for oral administration and is effective by aclinically applicable amount of dosage.

DISCLOSURE OF THE INVENTION

The inventor of the present invention, after comprehensive studies tofind a useful compound as a medicine for multiple sclerosis, has foundthat ibudilast attains the above object, and has completed the presentinvention.

The present invention relates to a medicine for multiple sclerosis,comprising ibudilast represented by the chemical formula (1) below asthe effective component:

The present invention relates also to a therapeutic treatment ofmultiple sclerosis by oral administration of a medicine containingibudilast as an effective component.

The inventor of the present invention has found first the effect ofibudilast, for treatment of multiple sclerosis. The ibudilast is usedwidely in Japan as a medicine, and a large amount of safety informationare available.

The ibudilast is a known compound represented by the above chemicalformula (1) (Japanese Patent Publication Sho-52-29318 (1977), U.S. Pat.No. 3,850,941 (1974), etc.), developed by Kyorin Pharmaceutical Co.,Ltd. as a medicine, and approved by Japanese Ministry of Health andWelfare for production and sale on January 1989. Since then, theibudilast is widely used as a medicine for bronchial asthma and acerebral circulation-improving agent. The known activities of theibudilast includes potentiation of action of prostacycline (Onoue etal., Gen.Pharmacol., 23,p1093,1992) and resulting increase of regeionalcerebral blood blow (Kudo et al., Folia Pharmacol. Jap.,85,p435,1995);leukotriene antagonism (Sato et al., Gen.Pharmacol., 17,p287, 1986;Ohashi et al., Int.Arch.Allergy.Immunol., 101,p.288,1993); suppressionof leukotriene liberation (Tamura et al., Basic and Clinical Report,20,p181,1986); inhibition of PDE (Souness et al., Brit.J.Pharmacol.,111,p1081,1994); and so forth. However, nothing has been known about theeffectiveness thereof on the multiple sclerosis.

Ibudilast can be administered to humans in a pharmaceutically knownformulation form and a dosing method, for example, in a form of powder,tablets, capsules, fine grains, granules, injection, solution, ointment,cataplasm, and so forth orally or parentally. An oral formulation ispreferred in consideration of ease in use by a patient. The amount ofthe dosage of ibudilast depends on the age and body weight of thepatient, conditions of the disease, and the method of the dosing. Theamount of the oral dosage ranges preferably from 100 to 200 mg, morepreferably from 10 to 60 mg in one dose, and dosing of two or threetimes per day is preferred.

BRIEF DESCRIPTION OF THE INVENTION

FIG. 1 is a graph showing the evaluation results by average clinicalscore for EAE model in Example 1 on each time after immunization.

FIG. 2 is a graph showing the change of the body weight in Example 1 oneach time after immunization.

FIG. 3 is a graph showing the evaluation results of average histologicscore in Example 2.

EXAMPLES

The effectiveness of ibudilast against multiple sclerosis is describedin detail by reference to Examples. Rats of an experimental autoimmuneencephalomyelitis (hereinafter referred to as EAE) model were used forevaluation of effect of ibudilast for amelioration of multiple sclerosis(Example 1). The EAE model is generally used as an animal model formultiple sclerosis (Ruddle et al., J.Exp.Med., 172,p1193,1990; Powell etal., Int.Immunol., 2,p539,1990; Olsson et al., J.Neuroimmunol., 40,p211,1992; Kartin et al., J.Exp.Med., 180,p2227,1994; and Selmaj et al.,ANN.Neurol., 30,p694,1991). Further, pathological evaluation wasconducted for confirming the ameliorating effect for the diseasecondition (Example 2). As the results, ibudilast was found to haveameliorating effect for the disease of the EAE model. The effect ofibudilast was confirmed histopathologically also.

Example 1

The disease ameliorating effect of ibudilast was investigated using ratsof a multiple sclerosis model (EAE model).

(1) Experimental Animal: DA Strain Rats (6 Rats in Each Group)

(2) Preparation of Model

The rats were injected subcutaneously with a Freund's complete adjuvantcontaining H37Ra Mycobacterium tuberculosis, and Myelin basic protein(MBP).

The rats of the control group were injected merely with the Freund'scomplete adjuvant. The experiment was conducted by taking as thereference the disease development in the control group. The observationwas conducted until 18 days after the disease onset.

(3) Method of Dosing

Ibudilast was administered through a feeding tube at a dosage of 2mg/kg, or 10 mg/kg once a day. The dosing was continued from the timebefore disease onset to the time after the disease onset. The controlgroup was dosed with physiological saline in the same manner.

(4) Evaluation of Effect

The disease ameliorating effect (clinical effect) of ibudilast wasscored and evaluated with the evaluation standard below.

Score 0: No symptom (normal)

Score 0.5: Mild paresis of the tail

Score 1: Limp tail

Score 2: Mild paraparesis of the hind limbs with unsteady gait

Score 3: Moderate paraparesis

Score 4: Paraplegia

(5) Results

In comparison with the control group, the 2 mg/kg ibudilast-treatedgroup showed tendency of amelioration of the clinical disease condition,and the 10 mg/kg ibudilast-treated group showed significantamelioration. Moreover, in the ibudilast-treated group, the diseaseonset was delayed (FIG. 1).

The rats of the 10 mg/kg-treated group which were improved significantlyin clinical disease conditions were suppressed significantly from bodyweight decrease (FIG. 2).

Thus the ibudilast showed a disease ameliorating effect and a bodyweight decrease prevention effect.

Example 2

The effect of ibudilast for rats of a multiple sclerosis model (EAEmodel) was investigated pathologically.

(1) Experimental Animal: DA Strain Rats (3 Rats in Each Group)

(2) Preparation of Model

The rats were injected subcutaneously with a Freund's complete adjuvantcontaining H37Ra Mycobacterium tuberculosis, and Myelin basic protein(MBP).

The rats of the control group were injected merely with the Freund'scomplete adjuvant.

(3) Method of Dosing

Ibudilast was administered through a feeding tube at a dosage of 10mg/kg once a day, which dosage showed the significant effect ofameliorating the disease condition. The rats of the control group weredosed with physiological saline in the same manner.

(4) Histological Evaluation

Twelve days after the immunization, the rats of ibudilast-treated groupand of the control group were anesthetized and were fixed withparaformaldehyde by transcardiac transfusion, and the lumbar part ofspinal cord was stained with hematoxylin-eosin to evaluate the extent ofinflammation.

(5) Evaluation of Effect (Histological Score)

Score 0: Normal

Score 1: Inflammatory cell cuffing limited to the perivascular spaces

Score 2: A few infiltration of inflammatory cells into spinal cordparenchyma

Score 3: Considerable infiltration of inflammatory cells into spinalcord parenchyma

Score 4: Marked infiltration of inflammatory cells into spinal cordparenchyma with destruction of the gray matter

(6) Result

The average score of the 10 mg/kg ibudilast-treated group was about 2.0,whereas that of the control group was 3.5.

Ibudilast showed significant effect histologically in comparison withthe control (FIG. 3).

This result supports the results of the experiment in [Example 1] ofamelioration of clinical disease conditions.

INDUSTRIAL APPLICABILITY

Ibudilast is confirmed to be effective to the EAE model. Therefore, itis useful as a remedy for multiple sclerosis with safety higher thanthat of steroids with a medical cost lower than that of interferon β.

What is claimed is:
 1. A method of treating multiple sclerosiscomprising oral administration of a medicine containing an effectivemultiple sclerosis treating amount of ibudilast to a subject in needthereof wherein ibudilast is represented by the chemical formula: